Sacubitril
| Evidence Level: L5 | Predicted Indications: 5 |
Table of Contents
Sacubitril: From Cardiovascular Use to Diabetic Nephropathy
One-Sentence Summary
Sacubitril is a neprilysin inhibitor, marketed in Canada as a single-ingredient product (for example, ENTRESTO) and used in combination with valsartan. The TxGNN model’s top-ranked predictions are rare genetic disorders with no supporting evidence. The best-supported candidate is diabetic nephropathy (TxGNN rank 3), backed by 1 registered clinical trial and 15 publications, mostly preclinical or indirect. This report evaluates diabetic nephropathy as the most actionable prediction. The two highest-scoring predictions have essentially no supporting evidence.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not available in the data compiled for this report (indication text is blank in the Canadian license records) |
| Predicted New Indication | Diabetic nephropathy (best-supported of the top 5 predictions; the top-ranked prediction is brain small vessel disease 1 with or without ocular anomalies) |
| TxGNN Prediction Score | 0.9950 (diabetic nephropathy); top-ranked prediction: 0.9958 |
| Evidence Level | L5 (preclinical and indirect/observational support plus one unreported Phase 4 trial) |
| Canada Market Status | Marketed (marketed DINs: 9 of 9) |
| Number of DINs | 9 (marketed: 9) |
| Recommended Decision | Hold (research question; see Conclusion) |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on known pharmacology, sacubitril is a prodrug whose active metabolite inhibits neprilysin, an enzyme that breaks down natriuretic peptides. It is marketed together with valsartan, an angiotensin receptor blocker (ARB).
For diabetic nephropathy, the rationale is biologically plausible:
- Valsartan blocks the renin-angiotensin system, which is already a cornerstone of diabetic kidney disease management.
- Sacubitril raises natriuretic peptide levels, which may reduce glomerular hypertension, oxidative stress, NF-κB-mediated inflammation, and fibrosis.
- Several rodent studies (db/db mice, KKAy mice, Zucker obese rats, streptozotocin-type models) report improved renal injury markers, and a podocyte cell study points to an Nrf2/HO-1 antioxidant pathway.
- A secondary analysis of the PARADIGM-HF trial examined renal function in patients with type 2 diabetes and heart failure, which provides indirect human data.
The other top predictions have weaker support. For brain small vessel disease 1 and the autosomal dominant hematuria-retinal arteriolar tortuosity-contractures syndrome, both rare COL4A1-related basement membrane disorders, no mechanism has been established. Rheumatoid arthritis and hemoglobinopathy likewise show no clear mechanistic link. These are model predictions only.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT06501651 | Phase 4 | Unknown | 297 | Hyper-Save study: randomized, controlled, multicenter comparison of sacubitril/valsartan versus valsartan over 12 weeks in patients with essential hypertension and type 2 diabetic nephropathy (2:1 randomization). No results posted. |
No clinical trials are registered for the other four predicted indications.
Literature Evidence
Selected publications for diabetic nephropathy (15 retrieved in total):
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 37549515 | 2023 | Clinical study (design not confirmed) | International Immunopharmacology | 112 diabetic nephropathy patients with hypertension; nifedipine plus sacubitril/valsartan compared with nifedipine plus valsartan |
| 29661699 | 2018 | Secondary analysis of PARADIGM-HF | Lancet Diabetes & Endocrinology | Effect of neprilysin inhibition on renal function in patients with type 2 diabetes and heart failure |
| 40416927 | 2025 | Clinical imaging study | Diabetes, Metabolic Syndrome and Obesity | BOLD-MRI assessment of sacubitril/valsartan renal effects in diabetic nephropathy patients |
| 34734359 | 2023 | Review/Observational | Heart Failure Reviews | Disease-modifying drugs in diabetic patients with heart failure with reduced ejection fraction |
| 37625003 | 2023 | Review | Diabetes Care | Update on therapy pillars slowing diabetic nephropathy progression |
| 35165832 | 2022 | Review | Current Hypertension Reports | Newer drugs for blood pressure reduction and hypertensive target organ damage |
| 35992034 | 2022 | Preclinical (rat) | Diabetes, Metabolic Syndrome and Obesity | Improved early diabetic nephropathy via NLRP3 inflammasome inhibition |
| 36589853 | 2022 | Preclinical (mouse) | Frontiers in Endocrinology | Improved diabetic kidney disease and modulated gut microbiota |
| 33870733 | 2021 | Preclinical (mouse) | Am J Physiol Renal Physiol | Differential effects versus valsartan in db/db and KKAy mice |
| 32596035 | 2020 | Preclinical (rat) | PeerJ | Reduced oxidative stress, NF-κB inflammation, and glomerulosclerosis |
For the top-ranked prediction (brain small vessel disease 1), the only publication retrieved (PMID 37169551, 2023, Heart) concerns sacubitril/valsartan in systemic right ventricular failure and is not relevant to the disease. For rheumatoid arthritis, the single publication (PMID 42266390, 2026) is a case report of golimumab-associated myocarditis, which does not support sacubitril efficacy.
Canada Market Information
| DIN | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| 02446936 | ENTRESTO | Not specified | Not specified |
| 02446928 | ENTRESTO | Not specified | Not specified |
| 02446944 | ENTRESTO | Not specified | Not specified |
| 02564432 | PMS-SACUBITRIL-VALSARTAN | Not specified | Not specified |
| 02549018 | SANDOZ SACUBITRIL-VALSARTAN | Not specified | Not specified |
Nine valid licenses are listed in total (ENTRESTO, PMS-SACUBITRIL-VALSARTAN, and SANDOZ SACUBITRIL-VALSARTAN products). Dosage form and indication details are not available in the compiled data.
Safety Considerations
Drug Interactions (6 moderate-level interactions identified):
- Nitisinone
- Rosuvastatin
- Simvastatin
- Cobicistat
- Revefenacin
- Alpelisib
Please refer to the package insert for warnings and contraindications.
Conclusion and Next Steps
Decision: Hold (diabetic nephropathy may be advanced as a research question)
Rationale:
- Diabetic nephropathy has a plausible mechanism and consistent preclinical support, but human evidence is indirect and the only registered Phase 4 trial has unknown status and no posted results. This falls short of Phase 2/3 RCT-level proof (L3).
- The two highest-scoring predictions (COL4A1-related disorders) and the rheumatoid arthritis and hemoglobinopathy predictions rest on model scores alone (L5) and should not be pursued.
- Safety label data (warnings and contraindications) could not be retrieved, so safety screening cannot yet proceed.
To proceed, the following is needed:
- Package insert warnings and contraindications from Health Canada, plus approved indication and dosage form details for each DIN
- Mechanism of action data from DrugBank
- Results or a status update for NCT06501651, and verification of its exact population and endpoints
- Full-text review of the clinical studies (PMID 37549515, 40416927, and the PARADIGM-HF secondary analysis) to confirm design and renal outcomes
- Safety considerations specific to diabetic nephropathy patients, such as renal function, potassium, and hypotension monitoring, in light of the identified drug interactions
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.